The objective of the proposed research is to examine in detail the roles played by components of complement and by polymorphonuclear leukocytes (PMN) in the pathogenesis of certain forms of lung injury in sheep characterized by increased permeability pulmonary edema. Experiments will be performed in vitro and in sheep with chronic lung lymph fistulas to test the hypothesis that PMN "stimulated" by complement (C5)-derived peptides (i.e., C5a and/or C5a des Arg) after the integrity of pulmonary microvascular endothelial cells. We plan to purify to homogeneity sheep C5a and C5a des Arg and to examine effects of these complement-derived peptides on sheep PMN in vitro. We will examine the adhesiveness of complement-stimulated sheep PMN as well as their ability to generate and/or release oxygen-derived free radicals, products of arachidonic acid, and lysosomal constituents. Finally, experiments will be performed in unanesthetized sheep to determine the effects on vascular tone and permeability of intravenously administered C5-derived peptides and to determine whether the lung injury in sheep that occurs in association with acute pancreatitis is mediated by C5-derived peptides and PMN. These studies should provide important new information concerning involvement of the complement system and PMN in the pathogenesis of certain forms of lung injury characterized by permeability pulmonary edema ("shock lung"). Elucidation of the pathogenesis of "shock lung" is sorely needed so that modern (and possibly future) therapeutic measures can be utilized appropriately.